Visual Inspection of Injectable Products: More than Sorting Good from Bad

John G. Shabushnig, Ph.D. Pfizer Global Quality Technical Services

February 9, 2005

Inspection Influences

Psychology

Regulatory

Inspection

Engineering Physics

Medicine & Physiology

Why Inspect?
Compendial Requirements Regulatory Requirements Physiological Implications Chemical and Microbiological Implications

US Pharmacopoeia
USP XXVII: <1> Injections - Foreign Matter and Particles
Every care should be exercised ... to prevent contamination with microorganisms and foreign material. Good pharmaceutical practice requires also that each final container ... be subjected individually to a physical inspection, whenever the nature of the container permits, and that every container whose contents show evidence of contamination with visible foreign material be rejected.

US Pharmacopoeia
USP XXVII: <1> Injections - Packaging
The container is made of material that permits inspection of the contents.

USP XXVII: <1> Injections - Constituted Solutions

Particulate Matter - Constitute the solution as directed in the labeling the solution is essentially free from particles of foreign matter that can be observed on visual inspection.

US Pharmacopoeia
USP XXIII: <788> Particulate Matter in Injections
Particulate matter consists of mobile, randomly-sourced, extraneous substances, other than gas bubbles, that can not be quantitated by chemical analysis due to the small amount Injectable solutions, including solutions constituted from sterile solids intended for parenteral use, is essentially free from particulate matter that can be observed on visual inspection. ...

Japanese Pharmacopoeia
JP XIV: 20. Foreign Insoluble Matter Test ...
... inspect with the unaided eye at a position of light intensity of approximately 1,000 luxes under an incandescent lamp: Injections must be clear and free from readily detectable foreign insoluble matters. As to Injections in plastic containers the inspection should be performed with the unaided eyes at a position of light intensity of approximately 8,000 to 10,000 luxes, with an incandescent lamp

EC GMP Annex 1 / WHO Annex 6

Finishing of Sterile Products
EC 90 / WHO 11.3. Filled containers of parenteral products should be inspected individually for extraneous contamination or other defects. When inspection is done visually, it should be done under suitable and controlled conditions of illumination and background. Operators doing the inspection should pass regular eye-sight checks, with spectacles if worn, and be allowed frequent breaks from inspection.

EC GMP Annex 1 / WHO Annex 6

Finishing of Sterile Products
EC 90 / WHO 11.3. Where other methods of inspection are used, the process should be validated and the performance of the equipment checked at intervals. Results should be recorded.

WHO International Pharmacopoeia

WHO International Pharmacopoeia

Apparatus
- Vertical matte black panel - Vertical non-glare white panel next to black panel - Adjustable lamp holder with shaded, white light source and a diffuser ( two 13W fluorescent tubes, each 525 mm (20.7 in) in length is suitable). illumination at the viewing point is between 2,000 and 3,750 lux for clear glass ampoules. Higher values are preferable for coloured glass and plastic containers.

WHO International Pharmacopoeia

Recommended procedure
- Gently swirl or invert each individual container, making sure that no air bubbles are introduced, and observe for about 5 seconds in front of the white panel. Repeat in front of the black panel. - Record the presence of any particles. Repeat the procedure for a further 19 containers. - The preparation fails if one or more particles are found in more than one container. - When applied to reconstituted solutions , the test fails if particles are found in more than two containers.

What is the Problem?

Ambiguity! Definition of visible
- Inspection conditions lighting, background, duration, magnification - size, shape and color

Definition of essentially free

Particulate Matter vs. Foreign Matter

Particulate matter is an intrinsic element of the manufacturing process. Intrinsic
- Formulation, Processing Equipment, Primary Package qualified product contact materials (e.g. stainless steel, aluminum, glass, rubber, silicone oil)

Extrinsic
- Environmental Contaminants insect parts, hair, fibers, paint, rust

Foreign Material Concerns

Physiological
- Most studies have been conducted with LVPs and particles <10um. These are generally trapped in the capillaries of the lungs. Smallest particles found in liver and spleen. Risk of blood vessel blockage from particles >50um. No direct clinical evidence of health risk from limited particle exposure. Animal studies generally conducted with massive particle loads (105 -1012/kg). - Very few reports of adverse reactions from particles in IM injections.

Foreign Material Concerns

Chemical
- Single 100um particle in 1mL dose is equivalent to an impurity level of 4 ppm (v/v)

Microbiological
- Particles can be carriers for microbiological contamination

Process Control
- Cosmetic assessment of quality

PDA TR #37 Task Force

Review critical variables in the inspection process Define visibility (of particulates) through reference inspection method
Manual, single container inspection 500 lux, 18% gray background No magnification Inspection duration TBD

PDA TR #37 Task Force

Review impact of probabalistic inspection results on acceptance sampling plans and associated AQL values. Review particle identification methods and their use in a risk-based inspection plan.

Particulate Risk Management Program Life Cycle

Sampling and Sampling and Process Process Monitoring Monitoring Optimize Optimize Manufacturing Manufacturing Process Process Develop/Update Develop/Update Historical Historical Profile Profile

Identify Identify Sources Sources

Establish/Update Establish/Update Control Control Parameters Parameters

Developing Historical Profiles

Particle frequency or the number of rejected units Particle classification
- common categories of matter - source of particles
Indigenous or intrinsic to the process Foreign or extrinsic to the process

Particle size

Particulate Sources
Particles originate from specific sources:
Bulk drug substance Utilities, Water, HVAC, Gases Manufacturing Equipment Processing or Filling Equipment Environment Personnel Cleaning Processes Container / Closure Systems

Preventive Measures
Filtration
- In-line during filling - At point of use

Vial and Stopper Washing Equipment Design and Operation Cleanroom Design and Operation
- Isolator/Barrier Technology

Inspection Technology

Inspection
Visual Stimulus Visual Size Visual Size Visual Visual System System Operation Operation Visual System Task Performance Cognitive Cognitive Component Component Visual Visual Performance Performance Task Task Performance Performance Output / / Output Unit Input Unit Input Productivity

Luminance Luminance Contrast Contrast

Color Color Contrast Contrast Retinal Retinal Image Image Quality Quality Retinal Retinal Illumination Illumination Motor Motor Component Component Visual Visual Discomfort Discomfort Expectations Expectations

Motivation Motivation

Cost Cost

Management Management

Personality Personality

From G. Salvendy, Handbook of Human Factors and Ergonomics, 2nd Edition

Critical Inspection Parameters

Lighting
Illumination Intensity Uniformity and Flicker Type

Background
- Black / White - 18% Gray

Presentation and Manipulation Pace

Illumination Intensity
JP
- 1,000 lux

WHO
- 2,000-3,750 lux

IESNA
- Difficult Inspection, visual tasks of low contrast and small size. 1,000 lux - Exacting Inspection, visual tasks near threshold. 3,000-10,000 lux

Aging and Relative Illuminance

1.0
Relative Illuminance

0.8 0.6 0.4 0.2 0.0

20

30

40
Age (Years)

50

60

From IESNA Lighting Handbook, 9th Edition

Illumination Type
Incandescent
- No flicker

Fluorescent
- Possible flicker
HF Ballast

- Diffuse

Tyndall
- Directional - Crack detection

Lighting
2003 1996 56% 45% 15% 25% 26% 25%

Fluorescent ................................. Incandescent ............................... Both ............................................. Intensity at container:

-

65-750 ft-candles / 215 ft-candles median 90-500 ft-candles / 225 ft-candles median 600-7,000 lux / 2,000 lux median 850-4,650 lux / 2,100 lux median

Manual Inspection
2003 1996 56% 80% 31% 45% 22% 4% 30% 25%

Paced .......................................... Magnification ......

- (1.3-5x, 2x avg.)

Clip/Grouped ...............................
- number per group (2-15, 6.5 avg.)

Polarizer ......................................

Manual Inspection Rate

Molded Glass Vials - 1 to 10 mL ..................... 0.7-4 sec / 1-20 sec / - 11 to 100 mL ................. 1-28 sec / 0.5-20 sec / - >100 mL ........................ 1-4 sec / 1-20 sec / 2 sec median 6 sec median 6 sec median 7 sec median 3 sec median 7 sec median

Manual Inspection Rate (cont.)

Tubing Glass Vials - 1 to 10 mL .................... 0.7-60 sec / 8 sec median 0.5-20 sec / 7 sec median - 11 to 100 mL ................ 1-60 sec / 15 sec median 0.5-20 sec / 8 sec median Glass Ampoules .......... 4-42 sec / 4 sec median 3-20 sec / 11 sec median

Inspection Standards

Inspection Myth #1
100% inspection means detection and elimination of all visible defects (e.g. particulate matter, cracks, etc.)
- Inspection is a probabilistic process. - Detection probability is dependant on inspection conditions and defect characteristics. - Particles <200um generally have a detection probability <100%.

Human Inspection Performance

Detection Probability (%) 100 80 Borchert Knapp Ryan Androver Borchert Melchore

RZ
60 40 20 0 0 50 100 Particle Size (um) 150 200

From Shabushnig, Melchore, Geiger, Chrai and Gerger, PDA Annual Meeting 1995

Inspection Myth #1
100% inspection means detection and elimination of all visible defects (e.g. particulate matter, cracks, etc.)
- Inspection is a probabilistic process. - Detection probability is dependant on inspection conditions and defect characteristics. - Particles <200um generally have a detection probability <100%.

Inspection Myth #2
Human manual inspection is a validatable process.
- Human inspectors are not validatable. - Qualified human inspectors can provide reliable performance. Defined selection and training criteria Controlled inspection conditions
- Lighting, Background, Duration - SOPs

Inspection Myth #3
Magnification always improves human manual inspection performance.
- Inspectors will move head position to minimize eyestrain during extended inspection, reducing apparent magnification. - Controlled studies have not found increased detection of particulates or container defects with 3x magnification.

Detection Rate with Magnification

5 mL No Mag Product Container Closure All Defects Good 50.0% 37.5% 62.3% 50.6% 0.5% Mag 37.5% 37.2% 54.2% 46.0% 0.9% 30 mL No Mag 18.6% 45.4% 72.5% 53.6% 2.0% Mag 18.6% 44.6% 68.2% 51.4% 0.6%

Semi-automated inspection at 55 VPM, lyo test set, n=1000, 3x mag

Inspection Myth #3
Magnification always improves human manual inspection performance.
- Inspectors will move head position to minimize eyestrain during extended inspection, reducing apparent magnification. - Controlled studies have not found increased detection of particulates or container defects with 3x magnification.

Conclusions
Current industry performance is generally at or beyond limits of medical risk. Compendial guidance is ambiguous. Zero defects is a valuable goal, not a practical limit for particulate matter. Need to develop practical limits based on risk assessment and process capability measures.

Acknowledgments
PDA TR #37 Task Force
Julius Z. Knapp R&D Associates Roy T. Cherris Bridge Associates International Russell E. Madsen The Williamsburg Group, LLC

Pfizer Inc
- Stephen J. Borchert - D. Scott Aldrich

Rap.ID Particle Systems, GmbH

- Markus Lankers